PROJECT SUMMARY/ABSTRACT Respiratory disease represents a major health burden around the globe, causing disease in hundreds of millions of people and resulting in four million premature deaths annually. Inorganic arsenic, an established toxicant and carcinogen, has been associated with numerous health outcomes, including cancer of the lung. Evidence on the impact of arsenic exposure on lung function and exacerbation of respiratory symptoms, however, is less conclusive; the limited evidence available suggests exposure is associated with increased respiratory symptoms and decreased lung function. Prospective studies and studies examining low-moderate levels (<50 g/L) of water arsenic exposure, the level relevant for US populations, are very limited. In addition, no intervention studies have investigated the impact of removing arsenic exposure on respiratory health. We aim to fill in these important gaps in research using existing data from the Strong Heart Study (SHS), a prospective cohort of American Indian men and women that has been ongoing since 1988, and from the Strong Heart Water Study (SHWS), an ongoing multi-level participatory intervention in adults and children to reduce arsenic exposure in drinking water from private wells in American Indian communities in North/South Dakota. First, in the SHS, we will evaluate: baseline arsenic (Visit 1) exposure, measured in urine, with lung function (Visit 2) as measured by forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC (N=3,253); changes in arsenic exposure from Visit 1 to Visit 2 with Visit 2 FEV1, FVC, and FEV1/FVC (n=380); and baseline arsenic exposure with Visit 3 respiratory symptoms in participants with asthma (n=435). Second, at the SHWS at baseline, we will evaluate: the association of arsenic exposure, measured in urine and water, with lung function as measured by FEV1, FVC, FEV1/FVC, peak expiratory flow (PEF) and forced expiratory flow (FEF 25-75%); respiratory symptoms wheeze, shortness of breath, cough, and phlegm, as measured by questionnaire; and airway inflammation, as measured by fractional exhaled nitric oxide (FeNO), in 400 participants including adults and adolescents. Third, in the SHWS follow up, we will evaluate the effect of the arsenic removal filter on changes in respiratory outcomes after installation, assessing change in arsenic level between baseline and six months and the following outcomes between baseline and six months: lung function, respiratory symptoms, and FeNO. Improved understanding of the relation of chronic ingestion of low-moderate arsenic in water and respiratory health and how a prevention intervention can be used to assess the benefits of removing environmental exposures is essential to mitigate the impact of arsenic exposure in a disproportionately exposed population in the United States.